Genetic Decoding May Bring Advances in Worldwide Fight Against Malaria

By NICHOLAS WADE

Published: October 3, 2002

Scientists have decoded the genomes, or full DNA, of the main malaria parasite and the mosquito that spreads it, two major goals seen as likely to kick-start a new campaign against the resurgent disease. Deaths from malaria are thought to number about 2.7 million a year.

The advance bolsters hopes for developing a new generation of malaria control methods, including new drugs and a vaccine, when the parasite and the mosquito are growing more resistant to standard measures.

Malaria was eradicated from the United States and many other subtropical countries in the 1960's with help from the powerful pesticide DDT and aggressive public health measures. New malaria attacks -- two teenagers were infected in Virginia last month -- have occurred in this country from time to time but the disease has never regained a foothold here.

In sub-Saharan Africa, however, malaria was only contained, and the containment methods are fast losing force. The parasite recently started to acquire resistance to the two principal drugs, chloroquine and Fansidar, and the mosquito in some places is growing immune to a cheap and effective means of control, pyrethroid-treated bed netting. Of the 500 million cases of the illness that occur a year, 90 percent are in Africa. The disease kills more than one million African children a year, according to the World Health Organization.

The decoding of the malaria parasite and mosquito genomes, reported this week in the journals Nature and Science, lays the foundation for a comprehensive set of attacks on the disease. The parasite's genome is of particular interest because it should enable researchers to select new targets for drugs, to thwart the means by which the microbe has built resistance to existing drugs and to discover some Achilles' heel that might be snared by a vaccine.

The mosquito's genome presents another opportunity, though one that lies further off, that of creating genetically engineered strains that would be immune to the parasite and capable of displacing all their native cousins in a region. Other clues in the genome may lead researchers to pinpoint the odor-detecting genes with which it sniffs out humans in preference to all other prey for its blood meals.

Biologists used to study organisms gene by gene, an approach that has yielded very partial insights. With the genomic area, the coding for all of an organism's thousands of genes is revealed at one stroke. Though interpretation of the data may take years, biologists in principle possess every trick and survival stratagem in a pathogen's playbook once its genome is deciphered.

Decoding the genome of Plasmodium falciparum, the most dangerous of the four single-cell parasites that cause malaria, took six years and cost about $20 million, paid for by the Wellcome Trust of London, the National Institutes of Health in Bethesda, Md., and other sources. Dr. Malcolm J. Gardner of the Institute for Genomic Research in Rockville, Md., led a large team of scientists there and at the Sanger Centre near Cambridge in England. Completion of the falciparum genome was first announced at a conference in Las Vegas in February.

The genome of Anopheles gambiae, the primary carrier of the parasite, was begun more recently and took a mere 15 months even though its genome is far larger -- some 278 million units of DNA encoding 14,000 genes compared with the parasite's 23 million units of DNA and 5,268 genes. The mosquito team was led by Dr. Robert A. Holt of Celera Genomics in Rockville. The $14 million cost was born by the National Institutes of Health, by Genoscope in France and other sources.

Malaria experts contend that knowledge of the parasite and mosquito genomes, with that of the human genome, will allow the complex interactions between the three species to be worked out in detail, revealing many opportunities for intervention.

''It can't be good for the parasite that we know all this,'' said Dr. Louis Miller, a malaria researcher at the National Institutes of Health.

But the new struggle against malaria is unlikely to be straightforward, given the extraordinary cunning of the parasite and the mosquito's intricate adaptation to its human prey. Chloroquine, a cheap and effective wonder drug, was used indiscriminately for years and is now failing. Years of attempts to create a malaria vaccine have produced one disappointment after another.

''One of the humbling things about this field is that there were great minds who worked on it but they haven't made a great dent in the problem,'' said Dr. Dyann F. Wirth, a malaria researcher at the Harvard School of Public Health.

But the decoding of the two genomes ''brings malaria into the modern biology era,'' Dr. Wirth said, and ''will greatly speed the development of much needed drugs.'' The parasite genome may also help vaccine designers even though, in her view, ''We don't know enough about the basic biology to predict if a vaccine will be successful. I think we are not as far along as some people have been led to believe.''

One evident success of the genome project, and an important aid to drug development, is that researchers have already been able to reconstruct the parasite's metabolism -- its operational set of biochemical reactions -- entirely by computer analysis of its genes and their predicted functions. The parasite is hard to grow and study in the laboratory and much of its metabolism has previously been obscure.

Researchers hope that a special organ possessed by the parasite but not by humans will contain many suitable targets for drugs. The organ, known as an apicoplast, is the relic of an ancient enslaved alga and performs vital though largely unknown tasks for the parasite.

Like other microbes, the malaria parasite has previously been studied the laborious way, one gene at a time. Having all 5,300 genes in hand has enabled biologists for the first time to tackle the organism at its full level of complexity. In one study published this week, researchers have analyzed which subset of the 5,300 genes is switched on at each of four stages in the parasite's devious career, as it switches from life in the mosquito's salivary glands, to the human liver, to repeated cycles in red blood cells and the bloodstream, and back to the mosquito's intestine for mating and egg formation.

But the genome sequence holds depressing news for vaccine makers at least in one sense, in showing the vast power of the parasite's system for dodging the immune system. Feasting inside red blood cells, it is invisible to the body's immune defenses except for an anchor protein it inserts into the blood cell's surface to tether the cell to a vessel wall. Even when the immune system detects the anchor protein's presence, the parasite can switch to any of 50 versions of the anchor gene in its genome, staying one step ahead of immune attack.